In this renewal application of the program project (revised), two additional faculty at the same institution, UCLA, have combined efforts with the ongoing three investigators. Continuing are Drs. Richard Olsen, Carolyn Houser, and Istvan Mody. New are Drs. Michael Fanselow and Tom Otis. The Program Project is named "Plasticity of GABA-mediated Inhibition". The research brings together expertise in biochemistry, behavior, electrophysiology, neuroanatomy, and molecular and cell biology. Program members will combine to approach important questions in basic neurobiology which would be difficult for any one individual. Several important topics in which plasticity of GABAergic inhibition plays a crucial role will be addressed. Each set of studies will involve interactions among several investigators as indicated: 1) Effects of neurosteroids on GABARmediated inhibition; 2) Effects of ethanol on specific types of GABAR-mediated inhibition; 3) Neuronal plasticity following withdrawal of GABAR modulators; 4) Post-translational modulation and trafficking of GABAR; 5) Homeostatic neuronal plasticity; 6) GABAR-mediated inhibition in learning; 7) Involvement of extrasynaptic alpha4/6-beta-delta subunit-containing GABAR-mediated tonic inhibition in the action of neurosteroids, ethanol, and anesthetics, and in various sorts of plasticity. Components in the program also will examine hippocampal inhibition, with a focus on alpha4delta-containing GABAR, and aspects of inhibition in hippocampus and cerebellum in the GABAR delta subunit knockout mice and other genetically engineered animals. One project will consider the balance of excitation and inhibition during and after plasticity-inducing activities with various time frames. Its predominant role in the brain makes GABA a major player in the normal plasticity mechanisms that accompany experiences. By subjecting rodents, or in some cases, cells and slices, to somewhat extraordinary experiences that are considered to involve GABA, we will investigate the molecular and cellular mechanisms of the long-term modifications resulting. Better understanding of plasticity phenomena involving GABA has high relevance to normal brain function and to disease processes and may suggest treatments. Most relevant are epilepsy, stress, anxiety, and panic disorders, sleep disorders, and drug dependence (alcohol and benzodiazepines). The complexity of the proposed experimental procedures requires the expertise of a team of investigators, each with a wide spectrum of analytical tools. Together, these tools yield a powerful combination of experimental approaches vested in the group rather than in any single team member. All members of the Program Project are committed to working together to successfully bridge the gap between behavior and molecular events in the CNS.